Mervyn Mer

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Department of Medicine & ICU

Johannesburg Hospital

University of the Witwatersrand

Corticosteroids in Severe CAP

Mervyn Mer


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Introduction

Much controversy and debate regarding the

use of corticosteroids (CS) in clinical medicine

CS use in CAP controversialand unclear


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Definition of Pneumonia

Inflammatorycondition of the lung parenchyma,

caused by an infectious agent/s

Introduction


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Introduction

Community-acquired pneumonia common

Leading infectious cause ofdeath

Consistently among top 5 causes of death in both

developed and under-developed countries At least 20% cases CAP will require hospitalisation

- 25% of these will require ICU admission

Mortality of up to 50%

Almirall J, et al. Eur Resp J 2000; 15: 757-763

Alvarez-Lemma F, Torres A. Curr Opin Crit Care 2004; 10: 369-74


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Introduction

Mortality rates CAP relatively unchanged past halfcentury

Landmark study: Austrian and Gold 1964- deaths occurring within 1st 5 days of rx

notdue to failure to eradicate micro-organism

- suggested due to specific inflammatory responseof host

Evans GM, Gainsford WF. Lancet 1938; 2: 14-19

Austrian R, Gold J. Ann Intern Med 1964; 60 :759-770


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Introduction

...inflammatory response of the host may be

more important than the specific micro-

organism causing the infection or the type ofantibiotic administered

Rano A, Torres A, et al. Curr Opin Infect Dis 2006; 19: 179-84


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Mechanism of Action

CS modulate the inflammatory response

Inhibit the production of key substances inthe inflammatory pathway which contribute

to vascular permeability, oedema, leucocyte

migration and fibrin deposition


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Mechanism of Action

CS modulate the inflammatory response

- halt activation of various transcription

factors including NF- KB

- occurs via an inhibitory action on histone

acetylation and stimulation of histone

deacetylation

Barnes PJ. Allergy 2001; 56: 928-36

Marik P. Chest 2009


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Histone deacetylationCS stimulate

CBP / p300

HAT

CS/GR

AP-1

STATs

NF-KB

Histone acetylationCS inhibit


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Feldman C, et al. SAMJ 2007; 97: 1295-1306


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Severe CAP

CURB-65 score


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Treatment of Severe CAP

Amoxicillin-clavulanate or2nd or 3rd generation cephalosporin

&

Aminoglycoside

&

Macrolide / azalideAlternative : Flouroquinolone + another agent

Management of CAP in Adults Guideline. Feldman C, et al. SAMJ 2007; 97: 1295-1306


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ATS / IDSA Guideline on CAP

Mandell LA, et al. Clin Infect Dis 2007; 44 Supp2: S27-72


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ATS / IDSA Guideline on CAP

Hypotensive, fluid resuscitated patients with

severe CAP should be screened for occult CIRCI

Mandell LA, et al. Clin Infect Dis 2007; 44 Supp2: S27-72


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History

Initial description

1956

Effects of hydrocortisone upon coursepneumococcal pneumonia treated with penicillin

Wagner HNJ, et al. Bull John Hopkins Hosp 1956; 98: 197-215


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Severe Community Acquired Pneumonia

(CAP)

Pneumonia leading cause

of community-acquired

infection requiring ICUadmission

Mortality remains high

despite advances in

antimicrobials &supportive measures


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Hydrocortisone in Severe CAP : Outcome

Outcome

variable

Placebo Hydrocortisone p Value

ICU mortality 7 (30%) 0 (0%) 0.009

Hospital

mortality

7 (30%) 0 (0%) 0.009

60-d mortality 8 (38%) 0 (0%) 0.001

Length of ICU

stay, d

18 (3-45) 10 (4-33) 0.01

Length ofhospital stay, d

21 (3-72) 13 (10-53) 0.03

Duration of MV 10 (2-44) 4 (1-27) 0.007

Confalonieri M , et al. AJRCCM 2005; 171: 242-48


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Hydrocortisone in Severe CAP

Patients treated HC alsoshowed significantimprovements in

- PaO2

: FiO2

ratio

- chest radiograph score

- MODS score

- CRP reduction

Dose : 200mg iv bolusfollowed by 10mg / hr x 7d

Confalonieri M ,et al. AJRCCM 2005; 171: 242-248


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Recent Reviews

Severe CAP : approach to therapy

- CS promising adjunct

CS infusion in patients with severe CAP

- powerful immunomodulatory effects

- seems to be associated with significantreduction in morbidity, mortality, hospitalisation

Confalonieri M, Trevisan R. Recenti Prog Med 2006; 97: 32-36

Pineda L, et al. Expert Opin Pharmacother 2007; 8: 593-606


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Recent Reviews

Associated inflammatory response in pneumonia: role ofadjunctive corticosteroids

- adjunctive treatment with CS probably indicated

in severe CAP

An update on the diagnosis of adrenal insufficiency & theuse of corticotherapy in critical illness

- possible role for CS in severe CAP

Thomas Z, et al. Ann Pharmacother 2007; 41: 1456-65

Rano A, Torres A, et al. Curr Opin Infect Dis 2006; 19: 179-184


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CS and Severe CAP

Systematic review 2008

No evidence adverse outcomes or harm

Moderate doses of CS safe

Consider particularly in patients with COPD

or asthma receiving antimicrobials

Salluh JIF, et al. Critical Care 2008; 12: R76


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CS & CAP Requiring Hospitalisation

Prospective randomized controlled Japanesestudy

Aim : assess effectiveness CS as adjunctivetherapy in CAP requiring hospitalization

31 adult patients

Adrenal function evaluated

Mikami K, et al. Lung 2007 185 (5): 249-55


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CS & CAP Requiring Hospitalisation

Results

- shorter duration ofiv antibiotics if received CS

- vital signs stabilized earlierin steroid group

- differences most prominent in moderate-severe subgp.- prevalence ofrelative adrenal insufficiency high : 43%

Conclusion

- in moderate-severe CAP, CS promote resolution ofclinical symptoms & reduce duration iv antibiotic rx

Mikami K, et al. Lung 2007 185 (5): 249-55


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CS and Severe CAP

Spanish retrospective observational study

Cohort of patients hospitalised with severe CAP

(classes IV & V Prognostic Severity Index score)

308 patients evaluated- 238 (77%) rx standard antimicrobial therapy

- 70 (23%) received antibiotics & systemic steroids

Clinical characteristics similar

Garcia-Vidal C, et al. Eur Resp J 2007; 30: 951-956


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CS and Severe CAP

Median dose of CS :- 45.7mg / 24 hours methylprednisolone

Results

- systemic steroids were independentlyassociated

with a decreased mortality

( odds ratio 0.287; 95% CI 0.113-0.732 )

Conclusion

- mortality decreased in patients with severe CAPwho received simultaneous administration of systemic

steroids along with antibiotic therapy

Garcia-Vidal C, et al. Eur Resp J 2007; 30: 951-956


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CS and Severe CAP

Severe sepsis

Adrenal insufficiency

- common

- up to 2/3rds of patients with severe CAP

admitted to ICU

Salluh J, et al. Intensive Care Med 2006; 32: 595-598


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Role of CS in Paediatrics

Severe Mycoplasma Pneumoniae Pneumonia

MP responsible for10-40% cases paediatric CAP

Occasionally progression to severe pneumonia despite

appropriate antibiotic therapy

Retrospective evaluation effect prednisolone

Dose : 1mg/kg x 3-7 days, tapered over 7 days

Lee KY, et al. Pediatr Pulmonol 2006; 41: 263-8


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Role of CS in Paediatrics

Severe Mycoplasma Pneumoniae Pneumonia

Results

- recipients afebrile within 24 hours

- improvement in clinical status and radiographically Conclusion

- CS rx temporally associated with clinical & radiographic

improvement- may be helpful for reducing morbidity

Lee KY, et al. Pediatr Pulmonol 2006; 41: 263-8


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CS in Other Pulmonary Infections

Data indicating benefit Pneumocystis Jirovecii pneumonia

Tuberculosis

Varicella-zoster virus

Hantavirus

Influenza virus

Severe acute respiratory syndrome (SARS)Rano A, et al. Curr Opin Infect Dis 2006; 19: 179-184

Cheng VCC, et al. J Infect 2004; 49: 262-273

Mer M, et al. Chest 1998; 114: 426-31


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Critical Determinants

Timing

Dose

Duration


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Factors Affecting Response to CS Treatment

Factors Affecting

Treatment Response

Prevention of

Potential Complications

Corticosteroid

Treatment

Infection

Surveillance

Avoidance of

Paralysis

Avoidance of

Rebound Inflammation

Timing of

InitiationDosage

Duration of

Treatment


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Cortisol Levels and CAP

Cortisol levels predictors of severity andoutcome in CAP

Similar to PSI

Better than routinely measured laboratory

parameters ( CRP, procalcitonin, leukocytes)

Free cortisol not superior to total cortisol wrt

prognostic accuracy in CAP

Christ-Crain M. Am J Respir Crit Care Med 2007; 176: 913-20


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New Data

Corticosteroids not effective in CAP

RDBP trial, 213 hospitalised patients

7 days of adjunctive prednisolone (40mg dly)

- did not improve outcome

- increased late failure in nonsevere CAP

Snijders D, et al. Am J Respir Crit Care Med 2010; 181: 975-82


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New Data

Limitations

73% patients CURB-65 2

Abrupt cessation of CS (rebound)

Benefit in more severely ill patients cannot be

excluded

Underpowered

No assessment of adrenal function

Editorial: CS if admitted ICU with severe CAP witheither shock or ALI

Snijders D, et al. Am J Respir Crit Care Med 2010; 181: 975-82

Meduri GU, Confalonieri M. Am J Respir Crit Care Med 2010; 181: 880-82


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Recent Meta-analyses

Corticosteroid treatment

Patients with severe sepsis (n = 1228)

Acute lung injury-acute respiratory distresssyndrome (n = 648)

Conclusions

- CS of benefitAnnane D, et al. JAMA 2009; 301: 2362-2375

Tang B, et al. Crit Care Med 2009; 37: 1594-1603


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Aggregate Data Randomised Trials

CS in patients with pneumonia requiring ICU Many with septic shock& / oracute lung injury

Significant reduction in short term mortality

- relative risk 0.40; p=0.03

Small size of trials

Confalonieri M, et al. Am J Respir Crit Care Med 2005; 171:242-248

Nawab Q, et al. Am J Respir Crit Care Med 2007;175: A594

Annane D, et al. JAMA 2002; 288: 862-871

Meduri GU, et al. Chest 2007; 131:954-963


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Consensus Guidelines

Patients admitted to ICU with severe CAP

with eithershockoracute lung injury

- CS indicated

Marik PE, et al. Crit Care Med 2008; 36:1937-1949


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Corticosteroids for Pneumonia

Cochrane Database Systems Review 2011

6 studies, 437 participants

CS improve oxygenation and reduce need for

mechanical ventilation in severe pneumonia

Hastened resolution of symptoms

Adverse events related to CS infrequent

Chen Y, et al. Cochrane Database Syst Rev 2011: CD007720


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Future

ESCAPe Trial

Extended Steroid (in) CAP(e)

Patients admitted to ICU with severe CAP Randomised trial; 1400 patients

Prolonged use low dose MP


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Conclusion

Encouraging data regarding use of CS in

severe CAP

They should be used in this setting Dose

Avoid in non-severe CAP

Timing, dose, duration are critical variables


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Never underestimate

the power of steroids

Umberto Meduri


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In the ICU

People Die,

Steroids Never Do


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Mervyn Mer

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